TGX-1214 - Combination Strategy for the Treatment of Advanced Pancreatic Cancer

TGX-1214 - 治疗晚期胰腺癌的联合策略

基本信息

批准号：
10607971
负责人：
Mansoor M Amiji
金额：
$ 58.31万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607971
关键词：
3-Dimensional Abraxane Acids Affect Animal Model Antibody Therapy Biodistribution CD8-Positive T-Lymphocytes California Canis familiaris Clinical Clinical Research Clinical Treatment Clinical Trials Collaborations Combined Modality Therapy Data Dedications Development Diagnosis Disease Docosahexaenoic Acids Dose Drug Combinations Drug Kinetics Evaluation Fibrosis Formulation Foundations Future Genetically Engineered Mouse Goals Growth Human Immune checkpoint inhibitor Immunotherapy In Vitro Industry KPC model Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Mission Modality Modeling Nanotechnology Oils Organoids Paclitaxel Pancreas Transplantation Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Phase I Clinical Trials Polyunsaturated Fatty Acids Pre-Clinical Model Qualifying Rattus Refractory Research Personnel Safety Scientist Stromal Neoplasm System T cell infiltration Taxoids Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Toxic effect Toxicology Treatment Efficacy Treatment outcome United States Universities Unresectable Water advanced pancreatic cancer anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy anti-cancer therapeutic cancer immunotherapy checkpoint inhibition chemotherapy clinical development clinical translation clinically relevant cytotoxicity density effective therapy efficacy evaluation experience gemcitabine immune cell infiltrate immune checkpoint immune checkpoint blockade immunogenic improved improved outcome in vivo industry partner innovation interest lead candidate multidisciplinary multimodality nanoemulsion nanomedicine next generation novel novel therapeutic intervention novel therapeutics pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic neoplasm personalized medicine rational design translatable strategy treatment strategy tumor tumor growth

项目摘要

Project Summary In this Industry-Academic Partnership R01 application, a multidisciplinary team of investigators from the University of California at Davis, TargaGenix and Northeastern University are proposing to develop a highly innovative combination treatment strategy for refractory tumors, such as pancreatic ductal adenocarcinoma (PDA). The proposed studies will leverage multi-disciplinary expertise of scientists and clinicians to develop effective PDA treatment paradigm based on the combination of TGX-1214 (a nanoemulsion of our lead next generation taxoid DHA-SBT-1214) with immune checkpoint inhibition. In preliminary studies, our novel lead agent DHA-SBT-1214 strongly inhibited pancreatic cancer growth in two preclinical models of pancreatic cancer (complete tumor regression in both models). In addition, we have recently documented that the combination of an anti-PD-L1 therapy with our novel chemotherapy drug DHA-SBT-1214 formulated in a nanoemulsion (TGX- 1214), significantly increased CD8+ T-cell infiltration and enhanced the therapeutic effects of the anti-PD-L1 antibody in a pancreatic cancer syngeneic model. It is noteworthy that TGX-1214 alone on combined with an anti-PD-L1 antibody therapy strongly reduced tumor growth to a higher extent than paclitaxel, nab-paclitaxel (Abraxane), gemcitabine, or single anti-PD-L1 antibody therapy groups. Moreover, in the clinically relevant KPC genetically-engineered mouse model of PDA, TGX-1214 reduced tumor fibrosis and increased of CD8+ T-cell infiltration. Importantly, TGX-1214 appears safe and present a high therapeutic window as indicated by GLP- toxicity studies in rats and dogs. Thus, these results indicate that TGX-1214 is safe and effective in multiple preclinical models of PDA; it stimulates the immunogenic potential of PDA and provides synergistic therapeutic effects with immune checkpoint blockade therapy, warranting further evaluation. Our long-term goal is to develop safe and effective treatment strategies for PDA to test in clinical trials and ultimately to be used in humans. Based on these novel findings, we hypothesize that a combination of TGX-1214 and immune checkpoint antibody therapy will provide superior efficacy with less toxicity. The specific aims of the study are: (1): To evaluate tumor- specific delivery, biodistribution, tumor stromal density modulation, and immune cell infiltration of TGX-1214 in clinically relevant animal models of PDA; (2): To determine the therapeutic efficacy and safety of the TGX-1214 along with anti-PD-L1 antibody therapy in two clinically relevant PDA animal models (orthotopically grafted pancreatic tumor organoids and KPC mice), and (3): To determine the efficacy of TGX-1214 as monotherapy in patients with treatment-refractory PDA. At the completion of these studies, we expect that TGX-1214 in combination with cancer immunotherapy, will become part of the personalized medicine revolution that is only now beginning and will become a significant part of the future treatment paradigms to eliminate the burden of PDA, providing positive benefits in long-term treatment outcomes.

项目摘要在这个行业 - 学术合作伙伴关系R01应用中，来自加利福尼亚大学戴维斯分校，塔尔戈尼克斯和东北大学提议开发高度难治性肿瘤的创新组合治疗策略，例如胰腺导管腺癌（PDA）。拟议的研究将利用科学家和临床医生的多学科专业知识来发展有效的PDA处理范例基于TGX-1214的组合（我们铅的纳米乳液下一步具有免疫检查点抑制作用的生成税素DHA-SBT-1214）。在初步研究中，我们的新领导代理DHA-SBT-1214在两个胰腺癌的临床前模型中强烈抑制胰腺癌的生长（在这两种模型中的完全肿瘤回归）。此外，我们最近记录了我们在纳米乳液中制定的新型化学疗法药物DHA-SBT-1214的抗PD-L1治疗（TGX- 1214），显着增加了CD8+ T细胞浸润并增强了抗PD-L1的治疗作用胰腺癌合成模型中的抗体。值得注意的是，单独使用TGX-1214与抗PD-L1抗体疗法大大降低了肿瘤的生长，比紫杉醇NAB-丙甲酰胺（Abraxane），吉西他滨或单一抗PD-L1抗体治疗组。此外，在临床相关的KPC中 PDA的遗传工程小鼠模型TGX-1214减少了肿瘤纤维化和CD8+ T细胞的增加浸润。重要的是，TGX-1214看起来很安全，并显示了GLP-指示的高治疗窗口大鼠和狗的毒性研究。因此，这些结果表明TGX-1214在多个中是安全有效的 PDA的临床前模型；它刺激PDA的免疫原性，并提供协同治疗性免疫检查点阻滞疗法的影响，需要进一步评估。我们的长期目标是发展 PDA在临床试验中测试的安全有效治疗策略，最终用于人类。基于在这些新颖的发现中，我们假设TGX-1214和免疫检查点抗体的组合治疗将提供较低的毒性效果。该研究的具体目的是：（1）：评估肿瘤 - 特定递送，生物分布，肿瘤基质密度调节和TGX-1214的免疫细胞浸润 PDA的临床相关动物模型；（2）：确定TGX-1214的治疗功效和安全性以及两种临床相关的PDA动物模型中的抗PD-L1抗体疗法（原位移植胰腺肿瘤器官和KPC小鼠）和（3）：确定TGX-1214作为单一疗法的功效治疗难治性PDA的患者。这些研究完成时，我们希望TGX-1214在结合癌症免疫疗法，将成为个性化医学革命的一部分现在开始并将成为未来治疗范式的重要组成部分，以消除 PDA，在长期治疗结果中提供积极的好处。